5-HT3 receptor antagonists

Abstract

The present invention provides 5-HT3 receptor antagonists of Formula (I): which are useful for the treatment of diseases treatable by inhibition of 5-HT3 receptor such as emesis, pain, drug addiction, neurodegenerative and psychiatric disorders, and GI disorders. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

What is claimed is: 
     
       1. A method of treating in a subject at least one disease, disorder, or condition treatable by inhibition of the 5-HT3 receptor, wherein the at least one disease, disorder, or condition treatable by inhibition of the 5-HT3 receptor is select from the group consisting of: emesis, migraine, substance abuse and addiction, anxiety, depression, eating disorders, schizophrenia, Parkinson's disease, cognitive dysfunction associated with Parkinson's disease, Huntington's Chorea, pre-senile dementia, Alzheimer's disease, pain, dyspepsia, gastroesophageal reflux disease, irritable bowel syndrome, atherosclerosis, tendomyopathies, and fibromyalgia, the method comprising
 (a) administering to the subject a compound of Formula (I): 
 
       
         
           
           
               
               
           
         
         
           wherein: 
           Z is O or NR a  where R a  is hydrogen or C 1-6  alkyl; 
           R 1  is a ring of the formula (a)-(h) below: 
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           R 2  is hydrogen, C 1-6  alkyl, or C 1-6  haloalkyl; 
           each R 3  is independently hydrogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, or halo and can be present on any carbon atom in the rings; 
           R 4  is pyridinyl or pyrazolyl optionally substituted with one or two substituents independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 1-6  alkoxy, cyano, or halo; 
           all of X 1 , X 2 , X 3 , and X 4  are CR 5 ; 
           each R 5  is independently hydrogen, C 1-6  alkyl, halo, hydroxy, or cyano provided that at least one of R 5  is hydrogen; and 
           X 5  is CR 6  where R 6  is hydrogen, C 1-6  alkyl, or halo; 
           or a pharmaceutically acceptable salt thereof or N-oxide thereof. 
         
       
     
     
       2. The method of  claim 1 , wherein R 1  is a ring of formula (a) or (d). 
     
     
       3. The method of  claim 1 , wherein R 1  is a ring of formula (e), (f), or (g). 
     
     
       4. The method of  claim 1 , wherein R 1  is a ring of formula (e). 
     
     
       5. The method of  claim 1 , wherein each R 3  is hydrogen. 
     
     
       6. The method of  claim 1 , wherein R 2  is hydrogen and each R 3  is hydrogen. 
     
     
       7. The method of  claim 1 , wherein each R 3  is independently hydrogen or methyl and R 2  is C 1-6  alkyl. 
     
     
       8. The method of  claim 1 , wherein R 2  is methyl and each R 3  is hydrogen. 
     
     
       9. The method of  claim 1 , wherein all of X 1 , X 2 , X 3 , and X 4  are CR 5  and each R 5  is hydrogen. 
     
     
       10. The method of  claim 1 , wherein the compound is selected from:
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyridin-3-yl)-1H-indole-3-carboxylate; 
 (1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-4-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-d3-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2-methylpyridin-3-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(4-methylpyridin-3-yl)-1H-indole-3-carboxamide; 
 1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(1-methyl-1H-pyrazol-3-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(1-methyl-1H-pyrazol-5-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(1-difluoromethyl)-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1H-pyrazol-4-yl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1H-pyrazol-4-yl)-1H-indole-3-carboxamide; or 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1H-pyrazol-4-yl)-1H-indole-3-carboxamide, 
 or a pharmaceutically acceptable salt of each-above mentioned compound. 
 
     
     
       11. The method of  claim 1 , wherein the compound is 1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide. 
     
     
       12. A method of inhibiting the 5-HT3 receptor in a subject, the method comprising
 (a) administering to the subject a compound of Formula (I): 
 
       
         
           
           
               
               
           
         
         
           wherein: 
           Z is O or NR a  where R a  is hydrogen or C 1-6  alkyl; 
           R 1  is a ring of the formula (a)-(h) below: 
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           R 2  is hydrogen, C 1-6  alkyl, or C 1-6  haloalkyl; 
           each R 3  is independently hydrogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, or halo and can be present on any carbon atom in the rings; 
           R 4  is pyridinyl or pyrazolyl optionally substituted with one or two substituents independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 1-6  alkoxy, cyano, or halo; 
           all of X 1 , X 2 , X 3 , and X 4  are CR 5 ; 
           each R 5  is independently hydrogen, C 1-6  alkyl, halo, hydroxy, or cyano provided that at least one of R 5  is hydrogen; and 
           X 5  is CR 6  where R 6  is hydrogen, C 1-6  alkyl, or halo; 
           or a pharmaceutically acceptable salt thereof or N-oxide thereof. 
         
       
     
     
       13. The method of  claim 12 , wherein the compound is 1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide. 
     
     
       14. The method of  claim 12 , wherein the compound is selected from:
 (1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(pyridin-3-yl)-1H-indole-3-carboxylate; 
 (1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-4-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-d 3 -3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-9-methyl-d3-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-2-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(2-methylpyridin-3-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(4-methylpyridin-3-yl)-1H-indole-3-carboxamide; 
 1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(1-methyl-1H-pyrazol-3-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(1-methyl-1H-pyrazol-5-yl)-N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 1-(1-difluoromethyl)-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(pyridin-3-yl)-1H-indole-3-carboxamide; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxamide; 
 (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl 1-(1H-pyrazol-4-yl)-1H-indole-3-carboxylate; 
 N-((1R,5S,7S)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1H-pyrazol-4-yl)-1H-indole-3-carboxamide; or 
 N-((1R,5S,7s)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1H-pyrazol-4-yl)-1H-indole-3-carboxamide; 
 or a pharmaceutically acceptable salt of each-above mentioned compound.